A comment on: “Proton pump inhibition for secondary hemochromatosis in hereditary anemia: a phase III placebo‐controlled randomized cross‐over clinical trial”
Authors: Wenke Moris, Ger H. Koek, Cees Th. B. M. van Deursen
Journal: American Journal of Hematology (2022)

Studies have shown that patients with HFE-related hemochromatosis needed significantly less phlebotomies to prevent iron re-accumulation in the maintenance phase of treatment, when using proton pump inhibitors (PPIs).1-3 In contrast, people without HFE-related hemochromatosis do not develop iron deficiency when taking PPIs chronically. To find an explanation for this difference we performed a proof of concept study with 10 HFE-related hemochromatosis patients and 10 healthy controls. We hypothesized that the adaptation of hepcidin levels plays an important role for this difference in iron absorption. In the normal physiology, reduction of acid secretion induced by PPIs leads to a decrease in the availability of Fe2+ to the small intestine and is counteracted by a decrease in hepcidin level facilitating an increase in iron uptake and export from the enterocyte. Since HFE-related hemochromatosis is characterized by an inappropriately low level of hepcidin, these patients cannot lower the hepcidin level any further to compensate for the decreased availability of Fe2+ resulting in a reduction of iron absorption. While people without HFE-related hemochromatosis have normal hepcidin levels allowing them to decrease hepcidin levels in response to a reduced availability of Fe2+, resulting in an unchanged level of iron absorption. In our study, we tested this hypothesis by measuring hepcidin and iron levels in both groups, before and after 7 days with administration of pantoprazole 40 mg once daily. We found that in HFE-related hemochromatosis patients, hepcidin levels were already low and did not evidently change after PPI use. In the healthy controls, a reduction of hepcidin levels was seen after 1 week use of PPIs. However this difference in hepcidin levels, was not statistically significant compared to baseline, probably due the biological variability of hepcidin in relation to the (small) number of participants of the study.4 It was with great interest that we read the paper by van Vuren et al.5 about the use of PPIs to treat iron overload in patients with nontransfusion-dependent hereditary anemias. The authors showed that in 30 patients with nontransfusion-dependent hereditary anemias with mild-to-moderate iron overload, esomeprazole 40 mg twice daily resulted in a statistically significant reduction in liver iron content (LIC). They found that in the group of patients with a low hepcidin/ferritin ratio the reduction of the LIC was significant versus a nonsignificant increase in LIC in the group with a high hepcidin/ferritin ratio. The hepcidin/ferritin ratio has two variables and a reduction can be caused by higher ferritin levels as well as by lower hepcidin levels (or a combination of both). It would be very interesting to study the effect of the PPI on the correlation between the hepcidin level as such and the delta LIC. Can the authors provide this information? If there is a good correlation between low hepcidin levels and reduction of the LIC this can be considered as supportive of our hypothesis. Moreover the use of PPIs in patients with secondary hemochromatosis can in that case be focused on patients with low hepcidin levels since they will be more likely to benefit. The authors declare no conflict of interest. Data availability statement is not applicable for the article.